Water-soluble dendritic cyclophanes (dendrophanes) of first (1, 4), second (2, 5), and third generation (3, 6) with poly(ether amide) branching and 12, 36, and 108 terminal carboxylate groups, respectively, were prepared by divergent synthesis, and their molecular recognition properties in aqueous solutions were investigated. Dendrophanes 1-3 incorporate as the initiator core a tetraoxa[6.1.6.l]paracyclophane 7 with a suitably sized cavity for inclusion compiexation of benzene or naphthalene derivatives. The initiator core in 4-6 is the [6.1.6.l]cyclophane 8 shaped by two naphthyl(pheny1)methane units with a cavity suitable for steroid incorporation. The syntheses of 1-6 involved sequential peptide coupling to monomer 9, followed by ester hydrolysis (Schemes 1 and 4).Purification by gel-permeation chromatography (GPC; Fig. 3) and full spectral characterization were accomplished at the stage of the intermediate poly(methy1 carboxylates) 10-12 and 23-25, respectively. The third-generation 108-ester 25 was also independently prepared by a semi-convergent synthetic strategy, starting from 4 (Scheme 5). All dendrophanes with terminal ester groups were obtained in pure form according to the I3C-NMR spectral criterion (Figs. 1 and 5). The MALDI-TOF mass spectra of the third-generation derivative 25 (mol. wt. 19328 D) displayed the molecular ion as base peak, accompanied by a series of ions [M -n(1041 7)]+, tentatively assigned as characteristic fragment ions of the poly(ether amide) cascade. A similar fragmentation pattern was also observed in the spectra of other higher-generation poly(ether amide) dendrimers. Attempts to prepare monodisperse fourth-generation dendrophanes by divergent synthesis failed. 'H-NMR and fluorescence binding titrations in basic aqueous buffer solutions showed that dendrophanes 1-3 complexed benzene and naphthalene derivatives, whereas 4-6 bound the steroid testosterone. Complexation occurred exclusively at the cavity-binding site of the central cyclophane core rather than in fluctuating voids in the dendritic branches, and the association strength was similar to that of the complexes formed by the initiator cores 7 and 8, respectively (Tables f and 3). Fluorescence titrations with 6-(p-tolnidino)naphthalene-2-sulfonate as fluorescent probe in aqueous buffer showed that the micropolarity at the cyclophane core in dendrophanes 1-3 becomes increasingly reduced with increasing size and density of the dendritic superstructure; the polarity at the core of the third-generation compound 3 is similar to that of EtOH (Table 2). Host-guest exchange kinetics were remarkably fast and, except for receptor 3, the stabilities of all dendrophane complexes could be evaluated by 'H-NMR titrations. The rapid complexation-decomplexation kinetics are explained by the specific attachment of the dendritic wedges to large, nanometer-sized cyclophane initiator cores, which generates apertures in the surrounding dendritic superstructure.
The dendritic cyclophanes (dendrophanes 1-3 containing a [6.1.6.l]paracyclophane as the initiator core embedded in dendritic poly(ether-amide) shells of first (l), second (2), and third (3) generation were prepared and characterized. The X-ray crystal-structure analyses of esters 7 and 4, derivatives of cyclophane core 9 and first-generation dendrophane 1, respectively, displayed open cavity binding sites suitable for the inclusion complexation of aromatic substrates. With their carboxylate surface groups, dendrophanes 1-3 were readily soluble in aqueous phosphate buffer (pH8.0), and the complexation of naphthalene derivatives was investigated by 'H-NMR and fluorescence titrations. The binding studies demonstrated that the cyclophane cavity remains open and accessible to appropriate substrates even at higher dendritic generations. The 1 : 1 complexes formed in aqueous buffer were of similar stability to those formed by the unbranched core 9 (I(, between 1000 and I0000 1 mol-I, 300 K). Investigations with the fluorescent probe 6-@-toluidino)naphthalene-2-sulfonate (12) showed that the micropolarity at the dendrophane core decreases with incrcasing generation number.Water-soluble cyclophanes with hydrophobic cavities are excellent synthetic receptors for apolar aliphatic and aromatic substrates [l] [2]. They contain wide open, solventexposed apertures by which substrates can penetrate rapidly, often in a nearly diffusioncontrolled way [3], into the binding site, and therefore possess model character for hydrophobic pockets and clefts at the surface of proteins. We became interested in developing model systems for apolar binding sites that are deeply buried within globular proteins and in investigating the influence of a shielding superstructure on kinetics and thermodynamics of inclusion complexation by a cyclophane. To reach this objective, we combined the rapidly developing dendrimer technology [4] [5] with cyclophane chemistry and describe here synthesis and binding properties of the first representatives 1-3 of the dendrophanes (dendr imer-cyclophanes)'). They possess a cyclophane receptor as initiator core to which dendritic shells with water solubility providing surface groups are covalently attached. In studies with 1-3, we intended to explore a ) whether the well-defined cyclophane recognition site remains open and effective at higher dendritic generations, or whether hydrophobic collapse causes the dendritic branches to occupy the binding site, b ) how the polarity of the binding site changes with increasing dendritic branching and ') A variety of dendrimers with receptor properties have been prepared; see [5]. However, the position of the incorporated guests in these systems is not well defined.
Cyclophanes 3 and 4 were prepared as initiator cores for the construction of dendrophanes (dendritic cyclophanes) 1 and 2, respectively, which mimic recognition sites buried in globular proteins. The tetraoxy[6.1.6.l]paracyclophane 3 was prepared by a short three-step route (Scheme 1) and possesses a cavity binding site shaped by two diphenylmethane units suitable for the inclusion of flat aromatic substrates such as benzene and naphthalene derivatives as was shown by 'H-NMR binding titrations in basic D,O phosphate buffer ( Table 1). The larger cyclophane 4, shaped by two wider naphthyl(pheny1)methane spacers, was prepared in a longer, ten-step synthesis (Scheme 2) which included as a key intermediate the tetrabromocyclophane 5. 'H-NMR Binding studies in basic borate buffer in D,O/CD,OD demonstrated that 4 is an efficient steroid receptor. In a series of steroids (Table I), complexation strength decreased with increasing substrate polarity and increasing number of polar substituents; in addition, electrostatic repulsion between carboxylate residues of host and guest also affected the binding affinity strongly. The conformationally flexible tetrabromocyclophane 5 displayed a pronounced tendency to form solid-state inclusion compounds of defined stoichiometry, which were analyzed by X-ray crystallography (Fig. 2). 1,2-Dichloroethane formed a cavity inclusion complex 5a with 1 : 1 stoichiometry, while in the 1 : 3 inclusion compound 5b with benzene, one guest is fully buried in the macrocyclic cavity and two others are positioned in channels between the cyclophanes in the crystal lattice. In the 1 :2 inclusion conipound 5c, two toluene molecules penetrate with their aromatic rings the macrocyclic cavity from opposite sides in an antiparallel fashion. On the other hand, p-xylene (= 1 ,Cdimethylbenzene) in the 1 : 1 compound 5d is sandwiched between the cyclophane molecules with its two Me groups penetrating the cavities of the two macrocycles. In the 1 :2 inclusion compound 5e with tetralin (= 1,2,3,4-tetrahydronaphthalene), both host and guest are statically disordered. The shape of the macrocycle in 5a-e depends strongly on the nature of the guest (Fig. 4). Characteristic for these compounds is the pronounced tendency of 5 to undergo regular stacking and to form channels for guest inclusion; these channels can infinitely extend across the macrocyclic cavities (Fig. 6) or in the crystal lattice between neighboring cyclophane stacks (Fig. 5). Also, the crystal lattice of 5c displays a remarkable zig-zag pattern of short Br . ' . 0 contacts between neighboring macrocycles (Fig. 7). 1. Introduction. -Over the past two decades, water-soluble, nanometer-sized cyclophanes have attracted large interest as synthetic receptors for apolar substrates [I -31 and, after suitable functionalization, as artificial enzymes [4]. They contain wide open, solvent-exposed apertures by which hydrophobic guests penetrate, often in a nearly diffusion-controlled way [I b], into the binding site, and, therefore, possess model character for h...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.